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(Design Cells/iStock)HEALTH

Scientists Successfully Turn Breast Cancer Cells Into Fat to Stop Them From Spreading

JACINTA BOWLER10 AUG 2019

Researchers have been able to coax human breast cancer cells to turn into fat cells in a new proof-of-concept study in mice.

To achieve this feat, the team exploited a weird pathway that metastasising cancer cells have; their results are just a first step, but it’s a truly promising approach.

When you cut your finger, or when a foetus grows organs, the epithelium cells begin to look less like themselves, and more ‘fluid’ – changing into a type of stem cell called a mesenchyme and then reforming into whatever cells the body needs.

This process is called epithelial-mesenchymal transition (EMT) and it’s been known for a while that cancer can use both this one and the opposite pathway called MET (mesenchymal‐to‐epithelial transition), to spread throughout the body and metastasise.

The researchers took mice implanted with an aggressive form of human breast cancer, and treated them with both a diabetic drug called rosiglitazone and a cancer treatment called trametinib.

Thanks to these drugs, when cancer cells used one of the above-mentioned transition pathways, instead of spreading they changed from cancer into fat cells – a process called adipogenesis.

“The models used in this study have allowed the evaluation of disseminating cancer cell adipogenesis in the immediate tumour surroundings,” the team wrote in their paper, published in January 2019.

“The results indicate that in a patient-relevant setting combined therapy with rosiglitazone and trametinib specifically targets cancer cells with increased plasticity and induces their adipogenesis.”

Although not every cancer cell changed into a fat cell, the ones that underwent adipogenesis didn’t change back.

“The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating,” said senior author Gerhard Christofori, a biochemist at the University of Basel, in Switzerland.

“As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells.”

So how does this work? Well, as a drug trametinib both increases the transition process of cells – such as cancer cells turning into stem cells – and then increases the conversion of those stem cells into fat cells.

Rosiglitazone was less important, but in combination with trametinib, it also helped the stem cells convert into fat cells.

“Adipogenic differentiation therapy with a combination of rosiglitazone and [trametinib] efficiently inhibits cancer cell invasion, dissemination, and metastasis formation in various preclinical mouse models of breast cancer,” the team wrote.

189942 cancer cells to fat cells

(Department of Biomedicine, University of Basel)

The image above shows this process, with the cancer cells tagged with a green fluorescent protein and normal red fat cell on the left. The cancer-turned-fat cells display as brown (on the right) because the red of the fat cells combines with the green of the protein cancer cell tag.

What’s exciting is that these two drugs are already FDA-approved, so it should be easier to get this type of treatment into clinical trials for actual people.

That’s exciting even despite the fact that we know many mouse-tested treatments don’t actually make it to, or fail, the clinical trial stage. The fact this worked on human cancer cells gives a little extra hope.

In the meantime, the team is investigating whether this therapy would work combined with chemotherapy, and whether it would apply to other types of cancers.

“In future, this innovative therapeutic approach could be used in combination with conventional chemotherapy to suppress both primary tumour growth and the formation of deadly metastases,” Christofori explained to the Press Association.

“The clinical evaluation of the treatment’s repressive effect on experimental breast cancer metastasis and, thus, of its potential in treating stage IV breast cancer will require adjuvant combinations with chemotherapy in advanced preclinical models,” the team wrote.

“Since we have used FDA-approved drugs to study the preclinical effect of the treatment, a clinical translation may be possible.”

The research has been published in Cancer Cell.

A version of this article was first published in January 2019.

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Sirius registra primeiras imagens com luz síncrotron de 4ª geração produzida no Brasil; VÍDEO

Pesquisadores verificaram estruturas de rocha e do coração de camundongo, e resultado surpreendeu pesquisadores. Laboratório em Campinas prevê início de experimentos em 2020.

Por Paulo Gonçalves, EPTV e G1 Campinas e Região

19/12/2019 20h40  Atualizado há um dia


00:00/02:20

Laboratório de Campinas faz primeiros testes com feixe de luz síncrotron

Laboratório de Campinas faz primeiros testes com feixe de luz síncrotron

Principal projeto científico do governo federal, o Sirius obteve imagens a partir dos primeiros feixes de luz síncrotron de 4ª geração produzidos no Brasil. Nos testes os pesquisadores observaram, por meio de microtomografias de raio X, estruturas de uma rocha e do coração de um camundongo. A previsão é que o superlaboratório em Campinas (SP) possa realizar experimentos no segundo semestre de 2020.

Os primeiros testes, realizados menos de um mês após a 1ª volta de elétrons completa na estrutura, surpreenderam a equipe, mesmo sendo realizados com uma potência 13 mil vezes inferior que a projetada para a máquina.

“Essas imagens foram surpreendentes. A gente não esperava que fosse conseguir imagens tão bacanas tão cedo, mas ainda é um teste e a máquina consegue entregar muito mais que isso”, afirma a pesquisadora Nathaly Archilha.

Detalhes do ventrículo de coração de camundongo obtida no teste de microtomografia de raio X do Sirius — Foto: Reprodução/Sirius/CNPEM
Detalhes do ventrículo de coração de camundongo obtida no teste de microtomografia de raio X do Sirius — Foto: Reprodução/Sirius/CNPEM

Detalhes do ventrículo de coração de camundongo obtida no teste de microtomografia de raio X do Sirius — Foto: Reprodução/Sirius/CNPEM

O que é o Sirius?

O Sirius é um laboratório de luz síncrotron de 4ª geração, que atua como uma espécie de “raio X superpotente” que analisa diversos tipos de materiais em escalas de átomos e moléculas. Atualmente, há apenas um laboratório de 4ª geração de luz síncrotron operando no mundo: o MAX-IV, na Suécia.

Para observar as estruturas, os cientistas aceleram os elétrons quase na velocidade da luz, fazendo com que percorram o túnel de 500 metros de comprimento 600 mil vezes por segundo. Depois, os elétrons são desviados para uma das estações de pesquisa, ou linhas de luz, para realizar os experimentos.

Esse desvio é realizado com a ajuda de imãs superpotentes, e eles são responsáveis por gerar a luz síncrotron. Apesar de extremamente brilhante, ela é invisível a olho nu. Segundo os cientistas, o feixe é 30 vezes mais fino que o diâmetro de um fio de cabelo.

‘Novo patamar’

Diretor-geral do Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), organização social responsável pelo Projeto Sirius, Antonio José Roque da Silva classificou o resultado como um feito, capaz de colocar a ciência brasileira em “um novo patamar”.

Financiado pelo Ministério de Ciência Tecnologia Inovações e Comunicações (MCTIC), 85% dos recursos foram investidos no País, em parceria com empresas nacionais.

“Sirius está ainda no início da sua fase de comissionamento, mas esses primeiros testes que permitiram gerar imagens de raios X nos dá a certeza que o futuro será muito brilhante. Seguimos entusiasmados para garantir o quanto antes condições de pesquisas inéditas para a comunidade científica do país”, disse.

Sirius: maior estrutura científica do país, instalada em Campinas (SP). — Foto: CNPEM/Sirius/Divulgação
Sirius: maior estrutura científica do país, instalada em Campinas (SP). — Foto: CNPEM/Sirius/Divulgação

Sirius: maior estrutura científica do país, instalada em Campinas (SP). — Foto: CNPEM/Sirius/Divulgação

O diretor do Sirius projetou que as primeiras linhas de luz da estrutura possam realizar experimentos no segundo semestre de 2020 – o atraso no orçamento, no entanto, impede a conclusão das 13 linhas de pesquisa previstas para o ano que vem. A equipe trabalha para que seis fiquem prontas no próximo ano.

Com o superlaboratório em funcionamento os cientistas esperam conseguir avanços em diversas áreas do conhecimento.

“Você tem as questões da área de saúde, entender melhor doenças, para desenvolver remédios, fármacos, vacinas. Você quer entender melhor as questões ligadas a baterias, para poder ter carros elétricos circulando com eficiência. Você quer novos materiais mais leves e resistentes para esses mesmos carros e aviões. Você quer poder produzir alimentos mais resistentes a mudanças climáticas, e é isso que um grande equipamento como esse pode fazer”, explica Roque.

Entenda como funciona o Sirius, o Laboratório de Luz Síncrotron — Foto: Infográfico: Juliane Monteiro, Igor Estrella e Rodrigo Cunha/G1
Entenda como funciona o Sirius, o Laboratório de Luz Síncrotron — Foto: Infográfico: Juliane Monteiro, Igor Estrella e Rodrigo Cunha/G1

Entenda como funciona o Sirius, o Laboratório de Luz Síncrotron — Foto: Infográfico: Juliane Monteiro, Igor Estrella e Rodrigo Cunha/G1

Veja mais notícias da região no G1 Campinas

Mais do G1PolíticaPF faz buscas em gabinete na Câmara, e STF determina afastamento de deputadoPolícia cumpre 4 mandados de prisão e 13 de busca na Paraíba e no DF. Operação foi autorizada pelo ministro Celso de Mello.Há 3 horasPolíticaAO VIVOFlamengo x LiverpoolFifa exibe troféus continentais no estádio do Mundial de Clubes; SIGADireto de Doha, acompanhe o clima que antecede à final em Doha, no Catar.Há 10 minutosflamengoAO VIVOSIGA: Flamenguistas se reúnem em rua de Botafogo antes da finalG1 acompanha a torcida pelo time nas ruas do Rio na decisão do Mundial.Há 8 minutosRio de JaneiroStarliner: o motivo pelo qual a cápsula para astronautas da Boeing terá de voltar à TerraDemonstração da cápsula foi interrompida devido a problemas técnicos;Ciência e SaúdeImagens da semana de 14 a 20 de dezembro de 2019MundoTúnel da Avenida Alberto Sá, no Bairro Papicu, será liberado para tráfego neste sábadoO novo equipamento permite a conexão direta da Avenida Alberto Sá com as ruas Tavares Coutinho e Ana Bilhar.CearáVEJA MAISúltimas notícias© Copyright 2000-2019 Globo Comunicação e Participações S.A.


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From the Lab to the Clinic: How Microfluidics Bridge Basic Sepsis Research and Clinical Diagnostics

Alec Salminen

From The Lab To The Clinic: How Microfluidics Bridge Basic Sepsis Research And Clinical Diagnostics

December 18, 2019

In a recent special communication edition of The Journal of the American Medical Association, sepsis was defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection1. This definition highlights the devastating nature of sepsis; arising from a simple infection and spiralling to an uncontrolled and often fatal immune response. Recent epidemiological studies place sepsis mortality at a staggering 18%, making it the leading cause of death in intensive care units2. This amounts to more than 30 million cases globally each year, nearly 6 million of which ending in the patient death [who.int]. Following largely disappointing and exceedingly expensive efforts in the development of sepsis-specific therapies, treatment of patients suffering from sepsis is left to clinical management of associated symptoms. Additionally, timely diagnosis of sepsis is imperative for effective treatment, however, most patients are presented to the clinic in an advanced, deteriorated state of disease. These substantial setbacks in the progression of sepsis treatment lead us to two major questions:

  1. How do we cost-effectively and accurately screen potential sepsis pharmaceuticals?
  2. Can we diagnose sepsis patients earlier to permit corrective intervention before irreversible disease progression?

We believe microfluidics can help answer these questions.

In the pursuit of developing a single, manufacturable system to answer our outstanding questions in sepsis research, we add an additional question to the problem: how can the field of microfluidics overcome the implicit challenges faced when bridging basic science research and clinical application? It is clear that communication between the research lab and the clinic (a field often referred to as translational biomedical science) can have an immediate impact on the health care system and in the context of sepsis, this increased dialogue has left a profound mark on the disease.

Microfluidics and Sepsis Research

Since the rise of conventional polydimethylsiloxane (PDMS) based microfluidic devices in the late 1990s and early 2000s, production of microphysiological systems (MPS) for a broad range of applications has increased, while the cost associated with these devices has declined. This large-scale development means that MPS are no longer primarily restricted to the labs of engineers and are now reaching the hands of knowledgeable biologists. From whole organ mimetics to blood-brain barrier models, microfluidic devices open the door to highly controlled studies on human cell lines and associated clinical samples. What is lost in physiological accuracy, is gained in simplicity and reproducibility, allowing for often complex or even unimaginable studies (when performed in vivo) at the lab bench. These points are emphasized in the context of sepsis research due to the following:

  • Previous studies in murine (a.k.a. mouse and rat) models of sepsis have highlighted important physiological differences between these experimental species and what really occurs in humans, particularly in the pathologic immune response defining the disease3.
  • Mass failure of immune-modulating drugs for the treatment of sepsis and the large financial burden associated with those shortcomings means labs are acutely aware of the need for cost-effective ways to screen for future therapeutics

For these reasons, microfluidics is a very attractive tool for sepsis research. In Dr. James McGrath’s lab at the University of Rochester, we utilize microfluidic devices to mimic the inflamed microvasculature related to sepsis pathophysiology and investigate the relationship between white blood cells (neutrophils) and the endothelial cells that line the vascular wall (Movie 1)4. The systems used herein, and others alike, allow for the highly controlled and meticulous study of the immune response in sepsis, all aimed at developing a better understanding of the disease, with the future hope of a cure. In doing so, we can maintain a significantly lower price point compared to studies performed in murine models.

Across the field, ‘lab-on-a-chip’ microfluidic systems are being exploited for drug discovery in all aspects of human disease because of their inherent controllable properties and low cost. These efforts were reviewed previously in Nature Drug Discovery5.Video Player00:0000:27

Movie 1. In our lab, microfluidic devices are assembled in a layer-by-layer fashion, allowing for human endothelial cell culture on a silicon nanomembrane (green/yellow chip). The resulting microvascular mimetics facilitate a live microscopy study of the white blood cell-lead immune response. The final frame depicts the nanoporous membrane utilized as the endothelial cell culture support.

Microfluidics in the Clinic

With low production costs, facile use, and increased throughput, microfluidic devices have left the confines of basic science research and entered the mainstream of clinical translation. Receiving major attention in a January 2019 issue of National Geographic, ‘lab-on-a-chip’ devices are highlighted as ‘the future of medicine’, with emphasis on the potential for personalized medicine. By incorporating patient cells and fluid samples to a specialized device, personalized medicine can permit patient-specific therapy and guided pharmaceuticals. Additionally, the requirement of minute sample volumes allows for increased experimentation/diagnostics on often precious patient samples or expensive reagents. These benefits have already proven impactful to the sepsis community: In a 2018 issue of Nature Biomedical Engineering, Ellett and colleagues describe a microfluidic platform that analyzes patient blood cell (neutrophil) motility to accurately diagnoses sepsis6. The device used immediately showcases the benefits of microfluidics in the clinic, as the diagnosis is performed using a single drop of blood, eliminating the need for large volume venipuncture draws or post-draw processing. In our lab, we are working on translating our MPS, namely, a stem cell-based mimetic of the blood-brain barrier, to act as an early-stage sepsis diagnostic. In addition to diagnostics, microfluidics has been suggested as an avenue to drugless sepsis treatment. Since the 1990s, it has been hypothesized that membrane-based, low footprint microfluidic devices may facilitate a process termed extracorporeal blood purification; a procedure in which harmful inflammatory factors are continuously filtered out of the blood, halting the maladaptive immune response. Given the applications presented here, the potential for impactful microfluidic technologies in the clinic is clear.

Bridging the Gap

As interest peaks in the use of microfluidics in the clinic, the question remains: how do we translate often meticulous device manufacturing to large scale production? This fabrication dilemma is most likely the demise of many microfluidic technologies developed in the lab. What is routine at a small scale in the cleanroom, may not be feasible at the necessary volumes to launch microfluidic devices into the clinic. Because of these concerns, many labs and clinics are less willing to adopt microfluidics in their work.

So how do we change this environment? Based on our recent experience, we suggest the following:

  • Design devices that may be used for a variety of applications (simplicity and functionality is key)
  • Work closely with microfluidics companies to adjust your designs for higher volume production goals
  • Involve other labs that work on similar products to share the benefits of these platforms
  • Talk to clinicians that would handle these devices to understand what problems are most important to them

In conclusion, microfluidics has the ability to open the door to truly translational science. In a single device, one can study the disease mechanism, develop targeted drugs, and diagnose patients. These multidisciplinary platforms effectively narrow the gap between basic science research and the clinic, paving the way to a future with a direct line of communication, from the patient straight to the lab.


References

1. Singer, M., Deutschman, C. S., Seymour, C. & et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA315, 801-810, doi:10.1001/jama.2016.0287 (2016).

2. Gotts, J. E. & Matthay, M. A. Sepsis: pathophysiology and clinical management. BMJ353, i1585, doi:10.1136/bmj.i1585 (2016).

3. Rittirsch, D., Hoesel, L. M. & Ward, P. A. The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol81, 137-143, doi:10.1189/jlb.0806542 (2007).

4. Salminen, A. T. et al. Ultrathin Dual-Scale Nano- and Microporous Membranes for Vascular Transmigration Models. Small15, e1804111, doi:10.1002/smll.201804111 (2019).

5. Dittrich, P. S. & Manz, A. Lab-on-a-chip: microfluidics in drug discovery. Nat Rev Drug Discov5, 210-218, doi:10.1038/nrd1985 (2006).

6. Ellett, F. et al. Diagnosis of sepsis from a drop of blood by measurement of spontaneous neutrophil motility in a microfluidic assay. Nature Biomedical Engineering2, 207-214, doi:10.1038/s41551-018-0208-z (2018).

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Alec Salminen

Alec Salminen

Alec Salminen is a Ph.D. candidate in the Department of Biomedical Engineering at the University of Rochester. His work, under Dr. James McGrath, involves the fabrication of silicon nanomembranes and microfluidic mimetics of the microvasculature to study the innate immune response in sepsis. Additionally, Alec works with a microfluidic manufacturer to fabricate devices for a variety of applications, including an early-stage sepsis diagnostic.

Elysia Masters, a Ph.D. candidate in the Department of Biomedical Engineering at the University of Rochester, aided in the writing of this post. More information on her work can be found below.

ResearchGate | LinkedInMicrofluidicsSepsis

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